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PDBsum entry 2vo6

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
2vo6
Jmol
Contents
Protein chains
338 a.a. *
20 a.a. *
Ligands
M05
Metals
_CL
Waters ×439
* Residue conservation analysis
PDB id:
2vo6
Name: Transferase
Title: Structure of pka-pkb chimera complexed with 4-(4- chlorobenzyl)-1-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin- 4-ylamine
Structure: Camp-dependent protein kinase, alpha-catalytic subunit. Chain: a. Synonym: pka c-alpha, protein kinase a. Engineered: yes. Mutation: yes. Camp-dependent protein kinase inhibitor alpha. Chain: i. Fragment: residues 6-25.
Source: Bos taurus. Bovine. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606
Resolution:
1.97Å     R-factor:   0.175     R-free:   0.229
Authors: J.J.Caldwell,T.G.Davies,A.Donald,T.Mchardy,M.G.Rowlands, G.W.Aherne,L.K.Hunter,K.Taylor,R.Ruddle,F.I.Raynaud, M.Verdonk,P.Workman,M.D.Garrett,I.Collins
Key ref: J.J.Caldwell et al. (2008). Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration. J Med Chem, 51, 2147-2157. PubMed id: 18345609 DOI: 10.1021/jm701437d
Date:
08-Feb-08     Release date:   08-Apr-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00517  (KAPCA_BOVIN) -  cAMP-dependent protein kinase catalytic subunit alpha
Seq:
Struc:
351 a.a.
338 a.a.*
Protein chain
Pfam   ArchSchema ?
P61925  (IPKA_HUMAN) -  cAMP-dependent protein kinase inhibitor alpha
Seq:
Struc:
76 a.a.
20 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain A: E.C.2.7.11.11  - cAMP-dependent protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     sperm midpiece   11 terms 
  Biological process     regulation of proteasomal protein catabolic process   19 terms 
  Biochemical function     nucleotide binding     14 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm701437d J Med Chem 51:2147-2157 (2008)
PubMed id: 18345609  
 
 
Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration.
J.J.Caldwell, T.G.Davies, A.Donald, T.McHardy, M.G.Rowlands, G.W.Aherne, L.K.Hunter, K.Taylor, R.Ruddle, F.I.Raynaud, M.Verdonk, P.Workman, M.D.Garrett, I.Collins.
 
  ABSTRACT  
 
Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3- d]pyrimidine inhibitors of PKBbeta with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21420856 R.Xu, A.Banka, J.F.Blake, I.S.Mitchell, E.M.Wallace, J.R.Bencsik, N.C.Kallan, K.L.Spencer, S.L.Gloor, M.Martinson, T.Risom, S.D.Gross, T.H.Morales, W.I.Wu, G.P.Vigers, B.J.Brandhuber, and N.J.Skelton (2011).
Discovery of spirocyclic sulfonamides as potent Akt inhibitors with exquisite selectivity against PKA.
  Bioorg Med Chem Lett, 21, 2335-2340.
PDB code: 3qkm
20471246 C.W.Murray, and T.L.Blundell (2010).
Structural biology in fragment-based drug design.
  Curr Opin Struct Biol, 20, 497-507.  
20151677 T.McHardy, J.J.Caldwell, K.M.Cheung, L.J.Hunter, K.Taylor, M.Rowlands, R.Ruddle, A.Henley, A.de Haven Brandon, M.Valenti, T.G.Davies, L.Fazal, L.Seavers, F.I.Raynaud, S.A.Eccles, G.W.Aherne, M.D.Garrett, and I.Collins (2010).
Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt).
  J Med Chem, 53, 2239-2249.
PDB codes: 2x37 2x39 2xh5
20205431 X.Zhang, A.C.Gibbs, C.H.Reynolds, M.B.Peters, and L.M.Westerhoff (2010).
Quantum mechanical pairwise decomposition analysis of protein kinase B inhibitors: validating a new tool for guiding drug design.
  J Chem Inf Model, 50, 651-661.  
19381851 C.O.Kappe, and D.Dallinger (2009).
Controlled microwave heating in modern organic synthesis: highlights from the 2004-2008 literature.
  Mol Divers, 13, 71.  
19443265 G.E.de Kloe, D.Bailey, R.Leurs, and I.J.de Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
19568781 L.A.Smyth, and I.Collins (2009).
Measuring and interpreting the selectivity of protein kinase inhibitors.
  J Chem Biol, 2, 131-151.  
19582301 R.Badorrey, E.Portaña, M.D.Díaz-de-Villegas, and J.A.Gálvez (2009).
Stereocontrolled synthesis of orthogonally protected 2-substituted 4-aminopiperidines.
  Org Biomol Chem, 7, 2912-2918.  
19339067 R.L.van Montfort, and P.Workman (2009).
Structure-based design of molecular cancer therapeutics.
  Trends Biotechnol, 27, 315-328.  
19645447 X.Yang, Q.Shi, Y.N.Liu, G.Zhao, K.F.Bastow, J.C.Lin, S.C.Yang, P.C.Yang, and K.H.Lee (2009).
Antitumor agents 268. Design, synthesis, and mechanistic studies of new 9-substituted phenanthrene-based tylophorine analogues as potent cytotoxic agents.
  J Med Chem, 52, 5262-5268.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.